Dissecting neural circuits for breathing patterns

剖析呼吸模式的神经回路

基本信息

批准号：
10319313
负责人：
Peng Li
金额：
$ 42.07万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319313
关键词：
Ablation Acute Afferent Pathways Blood gas Brain Brain Death Brain region Breathing COVID-19 Calcium Carotid Body Characteristics Clinical Research Coughing Development Drug abuse Emotional Esthesia Foreign Bodies Foundations Functional disorder Future Ganglia Gastrin releasing peptide Gene Expression Genetic Heterogeneity Homeostasis Hypoxia In Situ Hybridization Interoception Irritants Knowledge Label Lung Mediating Medical Molecular Mus Neural Pathways Neuraxis Neurons Nucleus solitarius Organ Outcome Panic Disorder Pathologic Pathway interactions Pattern Peripheral Pharmacotherapy Phase Phobias Physiological Play Population Post-Traumatic Stress Disorders Process RNA Research Respiratory physiology Role Seizures Signal Transduction Sleep Apnea Syndromes Specificity Stimulus Sudden infant death syndrome Synapses Tachykinin Techniques Testing Viral Visceral Work base cognitive process effective therapy experimental study expiration in vivo nervous system disorder neural circuit neuromechanism novel novel therapeutics optogenetics particle relating to nervous system response sensory stimulus single molecule single-cell RNA sequencing transcriptome

项目摘要

Proposal Summary Breathing is a vital function constantly regulated by the interoceptive signals from the body, and breathing patterns are known to impact emotional and cognitive processes. Breathing patterns with essential pulmonary interoception functions, such as sighing and coughing, are relevant to many pathological conditions, including sleep apnea, sudden infant death syndrome, excessive coughing, COVID-19, and various nervous system disorders, such as panic disorder, phobias, post-traumatic stress disorder, drug abuse, and even brain death. Therefore, there is a critical need to identify the neural mechanisms underlying the interoceptive control of breathing and how they fail under pathological conditions, to develop more effective treatments to breathing abnormalities. Sighing is an augmented breath with a deep, double-size inspiration that is dramatically induced in hypoxia. In contrast, coughing is a protective breathing pattern with a characteristic enlarged expiration phase triggered by tussive agents exposed in the airways. However, the neural circuits underlying these essential and discrete breathing patterns and how the brain interprets and integrates these different interoceptive sensory stimuli are largely unknown. In our preliminary studies, we identified two neuronal populations with distinct gene expression, connectivity, neural activity, and function, in the nucleus of the solitary tract (NTS), the first relay center in the brain that receives interoceptive afferent signals from the visceral organs. These neurons respectively mediate hypoxia induced sighing and tussive challenge induced coughing, two discrete breathing patterns associated with different interoceptive signals. Based on these findings, we propose to test our hypothesis that these two distinct NTS neurons are the key nodes in two segregated interoceptive neural circuits for controlling discrete breathing patterns and for representing these internal states, by receiving distinct afferent inputs and differently activating downstream brain circuits. We will integrate state-of-the-art techniques, including genetic targeting, viral-based neural circuit tracing, activity dependent neuron targeting, optogenetics and chemogenetics, genetic ablation, respiratory physiology, single molecule fluorescent RNA in situ hybridization, and in vivo calcium recording, to identify the neural circuits and pathways underlying these two interoceptive processes in vivo in freely moving mice. By focusing on these two distinct NTS neuron populations and neural circuits, we will delineate the distinct interoceptive afferent pathways from the periphery to the brain, identify the brain regions that mediate sighing and coughing, and define the higher brain regions for interpreting and integrating these distinct interoceptive signals. This work will provide novel molecular and cellular specificity for the interoceptive neural circuits for sighing and coughing respectively, and reveal the organizing principles of the NTS and the brain to ascertain differential interoceptive signals and inputs through the vagal afferent pathways. Furthermore, the proposed studies will also build the foundation for future clinical studies on the role of interoception in neuropathological conditions.

提案摘要呼吸是一项重要的功能，不断受到身体内感受信号的调节，众所周知，呼吸模式会影响情绪和认知过程。具有基本肺部内感受功能的呼吸模式（例如叹气和咳嗽）与许多病理状况相关，包括睡眠呼吸暂停、婴儿猝死综合症、过度咳嗽、COVID-19以及各种神经系统疾病，例如惊恐障碍、恐惧症、创伤后应激障碍、药物滥用，甚至脑死亡。因此，迫切需要确定呼吸内感受控制的神经机制以及它们在病理条件下如何失效，以开发更有效的呼吸异常治疗方法。叹息是一种增强的呼吸，在缺氧的情况下会显着诱发深沉的、双倍的吸气。相反，咳嗽是一种保护性呼吸模式，具有由气道中暴露的咳嗽因子引发的特征性呼气相延长。然而，这些基本且离散的呼吸模式背后的神经回路以及大脑如何解释和整合这些不同的内感受感觉刺激在很大程度上是未知的。在我们的初步研究中，我们在孤束核（NTS）中确定了两个具有不同基因表达、连接性、神经活动和功能的神经元群，孤束核是大脑中接收来自内脏器官的内感受传入信号的第一个中继中心。这些神经元分别介导缺氧引起的叹息和咳嗽引起的咳嗽，这是与不同内感受信号相关的两种离散呼吸模式。基于这些发现，我们建议检验我们的假设，即这两个不同的 NTS 神经元是两个分离的内感受神经回路中的关键节点，通过接收不同的传入输入和不同地激活下游大脑回路来控制离散的呼吸模式并表示这些内部状态。我们将整合最先进的技术，包括遗传靶向、基于病毒的神经回路追踪、活动依赖性神经元靶向、光遗传学和化学遗传学、基因消融、呼吸生理学、单分子荧光RNA原位杂交和体内钙记录，以识别自由移动小鼠体内这两种内感受过程背后的神经回路和通路。通过关注这两个不同的 NTS 神经元群和神经回路，我们将描绘从外周到大脑的不同内感受传入通路，识别介导叹气和咳嗽的大脑区域，并定义用于解释和整合这些不同的大脑区域。内感受信号。这项工作将为叹息和咳嗽的内感受神经回路提供新颖的分子和细胞特异性，并揭示 NTS 和大脑的组织原理，以确定通过迷走神经传入通路的差异内感受信号和输入。此外，拟议的研究还将为未来关于内感受在神经病理条件下的作用的临床研究奠定基础。